Synthesis of steroids



SYNTHEdlS (HF STERGIDS Josef Fried and Gordon H. Thomas, New

N. J., assignors to fllin Mathieson Clio tion, New York, N. 1., a corporation or lirnnswici-x, ll dorporm irgrriia No Drawing. Application February 7, 1957 Serial No. 638,675

4 Claims. (Cl. 260--3l37.3)

This invention relates to, and has for its object the provision of, a method of preparing 16-halo steroids of the androstaue (including the androstene) series.

The compounds prepared by the process of this invention are disclosed in our U. S. application, Serial No. 638,674, filed of even date herewith, and include the 16- halo steroids of the androstane series, particularly the 16- halo-A -androstene-3,l7-diones (e. g., l6ot-fluoro-A -androstene-3,17-dione; 16o-fluoro-A -andrstene-3,17-dione; and 1ofi-choloro-A -androstene-3,l7-dione). In accordance with the process of this invention, these compounds are prepared by oxidizing the corresponding l6-halo-lldesoxycorticosterone (i. e., 16halo-A -pregnene-l7a,21- diol-3,20-dione) as by treatment with a bismuthate (e. g., sodium bismuthate) or a hexavalent chromium compound (e. g., chromic acid). The reaction can be conducted at any normal temperature but, for ease in banding, is preferably conducted at ambient temperature. The reaction is preferably conducted in an organic solvent for the steroid reactant.

The l6-halo-A -pregnene-17a,2l-diol-3,20-diones employed as starting materials in the process of this invention can be prepared from the corresponding 16a,17aepoxy-A -pregnene-2l-ol-3,20-diones or the 21-esters thereof (such as the hydrocarbon carboxylic acid esters of less than ten carbon atoms, as exemplified by the lower alkanoic acids), in which case the esterifying acid must be hydrolyzed oil before or during the oxidation step. To prepare these starting materials, the 16,17-epoxide is reacted with the desired hydrogen halide (i. e., hydrochloric acid, hydrobromic acid and hydroiodic acid). It a 2l-ester is used in the reaction, it can then be saponified by treatment with an acid such as perchloric acid.

As stated in the aforementioned application, the compounds prepared by the process of this invention are physiogolically active steroids which possess androgenic activity.

The following Examples A and B illustrate the preparation of the starting materials used in the process of this invention (all temperatures being in centigrade):

EXAMPLE A I 6fi-chloro-A -pregnene-l 7a,21di0l-3,20-di0ne P EPARATION OF 1GB-CHLORO-N-PREGNENEJ70,21- R DIOL-3,20-DIONE 2l-ACETATE A solution of 1606,17m-c xido-A -pregnene-21-o1-3,20- dione ZI-acetate (6 g.) in glacial acetic acid (250 1111.) and concentrated hydrochloric acid (4 m1.) is allowed to stand at room temperature for 18 hours. The mixture is then diluted with water, the precipitated solid collected and crystallized from acetone-hexane. The resulting chlorohydrin (about 3.9 g.) melts at about 202205;

Patented Apr. .222, i958 (b) PREPARATION OF 16B-CHL0Ro-A -PREGNENE-l7m2l- D1OL-3,20-DIONE A suspension of 1op-chloro-A -pregnene-17a,2l-diol-3, 20-dione ZI-acetate (3.5 g.) in methanol (70 ml.) and 70% perchloric acid (1.75 ml.) is stirred at room temperature for 18 hours. The mixture is then diluted with water, the precipitated solid collected, washed with dilute sodium acetate solution and water, dried and crystallized from acetone-hexane. The deacetylated compound decomposes at about 162-166 (rapid heating);

max

Analysis-Calculated for C H O Cl (380.90): C, 66.20; H, 7.67. Found: C, 66.15; H, 7.85.

EXAMPLE B 16,B-bromo-h -pregnene-l 70:,2] dial-3 ,2 O-dione By substituting hydrobromic acid for the hydrochloric acid in the procedure of part a of Example A, there is obtained 16fl-bromo-A -pregnene-17u,2l-diol-3,20 dione.

In a similar manner, if hydrogen iodide is substituted for the hydrochloric acid in Example A, 16fi-i0do-A pregnene-l7a,2l-diol-3,20-dione is produced.

The following examples illustrate the process of this invention:

EXAMPLE 1 -011Zora-M nndrostene-BJ 7-di0ne A212. 237 mu (17,600);

Analysis.-Calculated for C H O Cl (320.85); C,

71.10; H, 7.85; Cl, 11.05. Found: C, 70.85; H, 7.74; CI, 10.89.

REEF 5.72, 0.01, 6.22;

EXAMPLE 2 By substituting one gram of 16B-bromo-A -pregnene- 17a,2l-diol-3,20-dione for the 16p-chloro-A -pregnenel7a,21diol3,20-dione in the procedure of Example 1, there is obtained 16,8-bromo-A -androstene-3,17-dione.

Similarly, l6fi-iodo-A pregnene, 1706,2l-diOl-3,20-dl0l16 yields l6/3-iodo-A -androstene-3,17-dione.

The invention may be otherwise variously embodied within the scope of the appended claims.

We claim:

1. A process for preparing 16halo-A -androstene-3, 17- dione, which comprises treating 16-halo-A -pregnene-17a, 2l-diol-3,20-dione with a compound selected from the group consisting of bismuthates and hexavalent chromium compounds, and recovering the 16-halo-A -androstene- 3,17-dione formed.

2. The process of claim 1, wherein the reactant is a bismuthate.

3. The process of claim 2, wherein the steroid reactant is 16,8-chloro-A -pregnene-l7tt,2l-dioi-3,20-dione.

4. The process of claim 2, wherein the steroid reactant is I6B-bromdA -pregnene-l7ot,2ldiol-3,20-dione.

No references cited. 

1. A PROCESS FOR PREPARING 16-HALO-$4-ANDROSTENE-3,17DIONE, WHICH COMPRISES TREATING 16-HALO-$4-PREGNENE-17A, 21-DIOL-3,20-DIONE WITH A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BISMUTHATES AND HEXAVALENT CHROMIUM COMPOUNDS, AND RECOVERING THE 16-HALO-$4-ANDROSTENE3,17-DIONE FORMED. 